Pulmonary manifestations are largely responsible for morbidity and mortality in cystic fibrosis (CF). This genetic disease is characterized by progressive lung damage due to chronic infection and exaggerated airway inflammation. Cystic fibrosis bronchial epithelial cells produce high levels of proinflammatory mediators, including interleukin 8 (IL-8), which causes the intense recruitment of neutrophils. The persistent influx of neutrophils into the airway is responsible of lung injury. The synthesis of several proinflammatory mediators is enhanced by hyper activation of intracellular transcription factor nuclear factor kappa B (NF-κB) in cystic fibrosis [1]. Currently, the only therapy recommended by Cystic Fibrosis Foundation (CFF) to lessen the excessive inflammatory response in the airways is a high dose of ibuprofen, a non-steroidal anti-inflammatory drug (NSAID). Two independent clinical trials showed significant preservation of Forced Expiratory Volume (FEV1) and other beneficial clinical effects of ibuprofen [2-4]. Unfortunately, adverse effects or concerns thereof have limited its clinical use. Mechanisms independent of cyclooxygenases inhibition have been proposed to explain the high dose ibuprofen effects and a recent study showed that ibuprofen inhibits the transcriptional activity of NF-κB in CF cells [5]. However, this inhibition is not accompanied by a decreased of IL-8 production. Therefore, it is crucial to develop new and safer anti-inflammatory medications and identify other molecules more effective at the IL-8 level in the context of cystic fibrosis.
Sulindac is used for the short and long term treatment of rheumatoid arthritis, ankylosing spondylitis, gouty arthritis, and osteoarthritis. It is a prodrogue that is metabolized by redox reaction in sulindac sulfide and sulindac sulfone derivatives. In cells, sulindac sulfide is generated by reduction by methionine sulfoxide reductase and inhibits cyclooxygenase activity. Oxidation of sulindac produces sulindac sulfone, a derivate that does not inhibit cyclooxygenase. A new feature of sulindac has been reported with the detection of anti-carcinogenic effects. The precise mechanisms by which sulindac compounds induce apoptosis are not known but seem independent of the inhibition of prostaglandin production. Indeed, sulindac sulfone, like sulindac sulfide, inhibits growth and induces apoptosis in a variety of human tumour cell lines [6,7], COX-2(%) fibroblasts [8] or human prostate cancer cells in nude mouse xenograft model [9]. Recent studies suggest that it may involve an increased production of ceramide, inhibition of the peroxisome proliferator-activated receptors, and/or inhibition of the NF-κB pathway [10]. All these targets are consistent in the context of cystic fibrosis.